Fluticasone Propionate Lotion

CUTIVATE® Lotion is a corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of atopic dermatitis in patients 3 months of age or older.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• HPA Axis Suppression and Other Adverse Endocrine Effects [see WARNINGS AND PRECAUTIONS]
• Local Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Concomitant Skin Infections [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience: Controlled Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In 2 multicenter vehicle-controlled clinical trials of once-daily application of CUTIVATE® Lotion by 196 adult and 242 pediatric patients, the total incidence of adverse reactions considered drug related by investigators was approximately 4%. These were local cutaneous reactions, usually mild and self-limiting, and consisted primarily of burning/stinging (2%). All other drug-related events occurred with an incidence of less than 1%, and included were contact dermatitis, exacerbation of atopic dermatitis, folliculitis of legs, pruritus, pustules on arm, rash, and skin infection. See Table 1.

The incidence of adverse reactions between the 242 pediatric subjects (age 3 months to < 17 years) and 196 adult subjects (17 years or older) was similar (4% and 5%, respectively).

Table 1: Adverse Reactions from Controlled Clinical Trials (N=438)

During the clinical trials, eczema herpeticum occurred in a 33-year old male patient treated with CUTIVATE® Lotion.

Table 2 summarizes all adverse events by body system that occurred in at least 1% of patients in either the drug or vehicle group in the phase 3 controlled clinical trials.

Table 2: Adverse Events Occurring in ≥ 1% of Patients from Either Arm from Controlled Clinical Trials (n=438)

Clinical Trials Experience: Pediatric Open Label Trials

In an open label HPA axis suppression trial of 44 pediatric subjects (ages ≥3 months to ≤ 6 years) CUTIVATE® Lotion was applied twice daily (rather than the indicated dosing regimen of once daily) to at least 35% of body surface area for 3 or 4 weeks. Subjects whose lesions cleared after 2 or 3 weeks of treatment continued to apply CUTIVATE® Lotion for an additional week. The overall incidence of adverse reactions was 14%. These were local, cutaneous reactions and included dry skin (7%), stinging at application site (5%), and excoriation (2%). Additionally, a 4-month-old patient treated with CUTIVATE® Lotion had marked elevations of the hepatic enzymes AST and ALT. [see Use in Specific Populations]

In another open label HPA axis suppression trial in which CUTIVATE® Lotion was also applied twice daily (rather than the indicated dosing regimen of once daily), 56 pediatric subjects (ages ≥3 months to 12 months), were enrolled [see Use in Specific Populations].

The adverse reactions included 2 cases of Herpes simplex at the application site (3.6%) and 3 cases of bacterial skin infections (5.4%).

Postmarketing Experience

The following local adverse reactions have been identified during post-approval use of CUTIVATE® Lotion: erythema, edema/swelling, and bleeding.

The following systemic adverse reactions have been identified during post-approval use of CUTIVATE® Cream and CUTIVATE® Ointment: immunosuppression/Pneumocystis jirovecii pneumonia/leukopenia/thrombocytopenia; hyperglycemia/ glycosuria; Cushing syndrome; generalized body edema/blurred vision; and acute urticarial reaction (edema, urticaria, pruritus, and throat swelling).

The following local adverse reactions have also been reported with the use of topical corticosteroids, and they may occur more frequently with the use of occlusive dressings or higher potency corticosteroids. These reactions include: acneiform eruptions, hypopigmentation, perioral dermatitis, skin atrophy, striae, hypertrichosis and miliaria.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Included as part of the PRECAUTIONS section.

Mechanism Of Action

Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action of CUTIVATE® Lotion in atopic dermatitis is unknown.

Pharmacodynamics

Trials performed with CUTIVATE® Lotion indicate that it is in the medium range of potency as demonstrated in vasoconstrictor trials in healthy subjects when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.

In an open label HPA axis suppression trial (Trial A), 42 pediatric subjects (ages 4 months to < 6 years) with moderate to severe atopic dermatitis covering ≥ 35% Body Surface Area (BSA) who were treated with an exaggerated dosing regimen of CUTIVATE® Lotion twice daily (rather than the indicated dosing regimen of once daily) for at least 3 to 4 weeks were assessed for HPA axis suppression. The mean BSA treated was 65%. None of the 40 evaluable subjects were suppressed. The criterion for HPA axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter at 30-minutes after cosyntropin stimulation.

Another open label HPA axis suppression trial (Trial B) enrolled 56 pediatric subjects (ages 3 months to 11 months) with moderate to severe atopic dermatitis covering ≥ 35% BSA. Subjects were treated with an exaggerated dosing regimen for of CUTIVATE® Lotion twice daily over a period of 3 or 4 weeks. The mean BSA treated was 54%. Out of 56 subjects, 49 were considered evaluable with respect to their adrenal axis function post-treatment. One of 49 subjects showed laboratory evidence of suppression immediately post treatment. The criterion for HPA axis suppression was a serum cortisol level of less than or equal to 18 micrograms per deciliter at 30-minutes after cosyntropin stimulation. Repeated test one week later showed the post cosyntropin stimulation testing serum cortisol returned to normal level (22.1 μg/dL). This 4-month old subject had a baseline treatment BSA of 94% and was reported to have received 100% of the twice-daily applications of CUTIVATE Lotion over the 27 day treatment period.

Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.

Plasma fluticasone levels were measured in a subset of subjects 2 to 5 years and 11 months of age in HPA axis suppression trial (Trial A) described above. A total of 13 (62%) of 21 subjects tested had measurable fluticasone at the end of 3 to 4 weeks of treatment. The mean ± SD fluticasone plasma concentration was 0.16 ± 0.23 ng/mL. Three subjects aged 3, 4, and 4 years had fluticasone concentrations over 0.30 ng/mL, with one of them having a concentration of 0.82 ng/mL. No data were obtained for subjects < 2 years of age.

The percentage of fluticasone propionate bound to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin.

No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate.

Fluticasone propionate is metabolized in the liver by cytochrome P450 3A4-mediated hydrolysis of the 5fluoromethyl carbothiolate grouping. This transformation occurs in 1 metabolic step to produce the inactive 17β-carboxylic acid metabolite, the only known metabolite detected in man. This metabolite has approximately 2000 times less affinity than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

Clinical Studies

CUTIVATE® Lotion applied once daily was superior to vehicle in the treatment of atopic dermatitis in two clinical trials. The two trials enrolled 438 subjects with atopic dermatitis aged 3 months and older, of which 169 subjects were selected as having clinically significant signs of erythema, infiltration/papulation, and erosion/oozing/crusting at baseline. Clinically significant was defined as having moderate or severe involvement for at least two of the three signs (erythema, infiltrations/papulation, or erosion/oozing/crusting), in at least 2 body regions. Subjects who had moderate to severe disease in a single body region were excluded from the analysis.

Table 3 presents the percentage of subjects who completely cleared of erythema, infiltration/papulation and erosion/oozing/crusting at Week 4 out of those subjects with clinically significant baseline signs.

Table 3: Complete Clearance Rate For Patients with Clinically Significant Signs at Baseline

Topical steroid medicine can be absorbed through the skin, which may cause steroid side effects throughout the body. Do not use fluticasone topical in larger amounts, or for longer than recommended by your doctor. Do not apply to your face, underarms, or groin area unless your doctor tells you to.

Do not cover treated skin areas with a bandage or other covering unless your doctor has told you to. If you are treating the diaper area of a baby, do not use plastic pants or tight-fitting diapers. Covering the skin that is treated with fluticasone topical can increase the amount of medicine your skin absorbs, which may lead to unwanted side effects.

Do not use this medication on a child without medical advice. Children are more likely to absorb large amounts of a topical steroid through the skin. Steroid absorption in children may cause unwanted side effects, or a delay in growth with long-term use.

Do not use fluticasone topical for longer than 2 weeks. Talk with your doctor if your symptoms do not improve, or if you develop signs of a bacterial, fungal, or viral skin infection.